Anti-inflammatory properties of montelukast, a leukotriene receptor antagonist in patients with asthma and nasal polyposis.

BACKGROUND: Leukotrienes, especially LTC4, are important inflammatory mediators in allergic and nonallergic inflammation of the entire airways. Of particular interest are numerous theories regarding the pathogenesis of aspirin intolerance with subsequent hyperproduction of leukotrienes and inhibition of cyclooxygenase. OBJECTIVE: To examine the influence of the cysteinyl-leukotriene receptor antagonist montelukast on clinical symptoms and inflammatory markers in nasal lavage fluid in patients with bronchial asthma and nasal polyps, and determine its dependency on aspirin sensitization. METHODS: Twenty-four patients (7 women, 17 men; median age, 55.5 years) with nasal polyps and controlled asthma (n=12 with aspirin intolerance) were treated with 10 mg montelukast once daily for 6 weeks in a blinded, placebo-controlled fashion. The placebo phase was randomly assigned 4 weeks before (n=12) or after treatment (n=12). Symptom score, rhinoendoscopy, rhinomanometry, smears for eosinophils, and nasal lavages for the determination of different mediators were performed. RESULTS: Compared to placebo, there were significant improvements in the nasal symptom score and airflow limitation as well as a reduction in the inflammatory mediators in nasal lavage fluid after treatment. Furthermore, reduced eosinophils in nasal smears and peripheral blood were observed 2 and 6 weeks after treatment. CONCLUSION: Leukotriene 1 receptor blockade led to a significant decrease in eosinophil inflammation accompanied by a reduction in other mediators such as neurokinin A and substance P in the nasal lavage fluid of patients with nasal polyps and asthma, with or without aspirin intolerance.

SA14867, a newly synthesized kappa-opioid receptor agonist with antinociceptive and antipruritic effects.

SA14867 ((+)-3-Acetyl-6-chloro-2-[2-(3-(N-(2-ethoxyethyl)-N-isopropylamino)propoxy)-5-methoxyphenyl]benzothiazoline O,O'-diacetyl-L-tartrate), a selective kappa-opioid receptor agonist, was synthesized and its antinociceptive and antipruritic effects were investigated. In a functional binding assay, SA14867 showed approximately more than 31,000 and 2200 fold higher affinity for the kappa-opioid receptor than for the mu- and delta-opioid receptors, respectively. SA14867 inhibited acetic acid-induced writhing and formalin test results after oral administration. The ED(50) values of SA14867 for acetic acid-induced writhing and for formalin test first phase and second phase were 1.9, 9.4, and 6.4 mg/kg, respectively. These values were smaller than those of asimadoline, U-50488H, and tramadol. SA14867 also showed antinociceptive effects in silver nitrate-induced arthritis that were as strong as U-50488H, tramadol, and morphine, and were stronger than asimadoline. The ED(50) value of SA14867 for hyperalgesia of arthritis was approximately 10 mg/kg. In addition, SA14867 showed antipruritic effects on 5-hydroperoxyeicosatetraenoic acid (HPETE) and substance P-induced pruritic models at 1 to 3 mg/kg. SA14867 also attenuated scratching reactions in a morphine-induced pruritic model in monkeys. Some of the inhibitory effects of SA14867 on nociceptive and pruritic models were attenuated by a kappa-opioid receptor antagonist, nor-BNI. These results suggest that SA14867 is a potential antinociceptive and antipruritic drug.

Impact of asthma controller medications on clinical, economic, and patient-reported outcomes.

OBJECTIVE: To comprehensively evaluate clinical, economic, and patient-reported outcomes associated with various therapeutic classes of asthma controller medications. PATIENTS AND METHODS: This observational study, which used administrative claims data from US commercial health plans, included patients with asthma aged 18 through 64 years who filled a prescription for at least 1 asthma controller medication from September 1, 2003, through August 31, 2005. Outcome metrics included the use of short-acting beta-agonists (SABAs), the use of oral corticosteroids, inpatient (INP)/emergency department (ED) visits, and asthma-related health care costs. A subset of 5000 patients was randomly selected for a survey using the Mini-Asthma Quality of Life Questionnaire, the Work Productivity and Activity Impairment questionnaire, and the Asthma Therapy Assessment Questionnaire. RESULTS: Of 56,168 eligible patients, 823 returned completed questionnaires. Compared with inhaled corticosteroids (ICSs), leukotriene modifiers (LMs) were associated with lower odds of INP/ED visits (odds ratio [OR], 0.80; P<.001), lower odds of using 6 or more SABA canisters (OR, 0.81; P<.001), and higher annual cost ($193; P<.001). In the subgroup analysis of adherent patients, LMs were associated with higher odds of INP/ED visits (OR, 1.74; P=.04), lower odds of using 6 or more SABA canisters (OR, 0.46; P<.001), and higher annual cost ($235; P<.001). Inhaled corticosteroids and LMs had a comparable impact on all patient-reported outcomes. For combination therapy, ICS plus a long-acting beta-agonist consistently showed at least equivalent or better outcomes in the use of SABAs and oral corticosteroids, the risk of INP/ED visits, cost, asthma control level, quality of life, and impairment in productivity and activity. CONCLUSION: Inhaled corticosteroids were associated with a lower risk of INP/ED visits, and a lower cost if adherence was achieved. When adherence cannot be achieved, LMs may be a reasonable alternative. Combination therapy with ICS plus a long-acting beta-agonist was associated with better or equivalent clinical, economic, and patient-reported outcomes.

Analysis of the effectiveness and cost benefit of leukotriene modifiers in adults with asthma in the Ohio Medicaid population.

OBJECTIVE: The objectives of this research were to (1) determine the association of the use of leukotriene modifiers (LMs) with 3 clinical outcome measures that can serve as proxy measures of effectiveness: subsequent emergency room visits, hospitalizations, and steroid bursts, and (2) estimate whether LM use compared with nonuse is cost beneficial from a Medicaid payer perspective. METHODS: This was a retrospective, longitudinal study of asthma patients in the fee-for-service Ohio Medicaid program. The study population included 5,541 adult patients who were identified as having a claim containing an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code for asthma (code 493.xx, excluding 493.2x) in 2001. Logistic regression, controlling for selection bias through the use of propensity scores, was used to determine the association of LM use on 3 outcome measures: emergency room visits, hospitalizations, and steroid bursts. An oral steroid burst was defined as a pharmacy claim for oral prednisone in the date range from 1 day before to 3 days after an office visit that has an ICD-9-CM code for asthma. A cost-benefit analysis was also performed. RESULTS: During the prestudy period, the LM users had higher total medical costs of $72.06 per patient per month (PPPM, $170.60 vs. $98.54, P <0.001). During the outcome period, there was no significant association between LM use and emergency room visits (odds ratio [OR] 1.09; 95% confidence interval [CI], 0.84-1.38), hospitalizations (OR 1.02; 95% CI, 0.66-1.59), or steroid bursts (OR 1.30; 95% CI, 0.89-1.90). Because LM use was not more effective than nonuse and is more expensive than nonuse, a situation of dominance prevails. The mean cost difference in the 3 primary outcome measures between LM users and nonusers was $1.63 PPPM ($34.93 vs. $33.30, P=0.019). CONCLUSION: In this study of adult Medicaid asthma patients, users of LMs did not have greater asthma control as measured by emergency room visits, hospitalizations, or steroid bursts. In this cohort of adult asthma patients with at least 1 asthma medication, there does not appear to be any cost offsets to the Ohio Medicaid program associated with the use of LMs. The use of LMs was associated with higher total costs for asthma care.

Inhibidores de los leucotrienos: los nuevos antiinflamatorios en el tratamiento de la artrosis / Leukotriene inhibitors: the new anti-inflammatory agents in the treatment of osteoarthritis

No disponible

Cysteinyl leukotrienes regulate dendritic cell functions in a murine model of asthma.

Dendritic cells (DCs) act as APCs in the airway and play a critical role in allergy. Cysteinyl leukotrienes (cysLTs) synthesized from arachidonic acid are primary mediators of immediate asthmatic reaction. The aim of this study was to investigate the effects of cysLTs on Dermatophagoides farinae (Der f)-pulsed mouse myeloid DCs in inducing allergic airway inflammation in vitro and in vivo. Control DC (medium-pulsed), Der f-pulsed DC, cysLT-pulsed DC, Der f- and cysLT-pulsed DC, and Der f-pulsed and cysLT receptor antagonist (LTRA)-treated DC were prepared from murine bone marrow, and the production of cytokines ws compared. Subsequently, these DCs were intranasally instilled into another group of naive mice, followed by intranasal Der f challenge to induce allergic airway inflammation in vivo. Der f-pulsed DC produced significantly higher amounts of IL-10 and IL-12 compared with control DC. Der f- and cysLT-pulsed DC further increased IL-10 production compared with Der f-pulsed DC. In contrast, treatment of Der f-pulsed DC with LTRA increased IL-12 and decreased IL-10. Intranasal instillation of Der f-pulsed DC resulted in airway eosinophilia associated with a significant rise in IL-5 levels in the airway compared with control DC. Pulmonary eosinophilia and excess IL-5 were further enhanced in Der f- and cysLT-pulsed DC-harboring mice. In contrast, Der f-pulsed and LTRA-treated DC significantly inhibited airway eosinophilia, reduced IL-5, and increased IFN-gamma in the airway. Our results suggest that cysLTs play an important role in the development of allergic airway inflammation by regulating the immunomodulatory functions of DCs.

Treatment effectiveness of inhaled corticosteroids and leukotriene modifiers for patients with asthma: an analysis from managed care data.

We compared measures of treatment effectiveness when inhaled corticosteroids (ICSs) or leukotriene modifiers (LMs) were used as controller monotherapy for asthma. Asthma patients aged 6-55 years initiating ICS or LM monotherapy between July 1998 and June 1999 (index prescription) were identified using a managed care claims database. Asthma-related hospitalizations, emergency department (ED) visits, and use of short-acting beta-agonists and oral corticosteroids (OCSs) were assessed as proxies for treatment effectiveness. Propensity score was used to adjust for baseline differences between treatment cohorts. The change in the annual rate of claims from the preindex to postindex period for each measure was compared across treatment groups. Logistic regression models of the postindex composite events (hospitalization and/or ED) and OCS use were estimated. Nine hundred sixty patients were initiated on LMs (n = 153) and ICSs (n = 807). The mean annual rate of claims for OCSs increased in the ICS group (0.2) but was unchanged in the LM group (adjusted mean difference in change, 0.2; 95% CI, 0.05-0.4; p = 0.01). The mean annual rate of claims for short-acting beta-agonists increased in both the ICS and LM groups by 1.1 and 0.5, respectively (adjusted mean difference in change, 0.6; 95% CI, -0.06. 1.1; p = 0.08). Similar changes in annualized rates of claims for hospitalizations and ED visits were observed between treatment groups. In logistic regression models, greater odds of postindex OCS use was observed among the ICS group (odds ratio for ICS versus LM = 1.7; 95% CI, 1.04-2.8; p = 0.04). No association between treatment groups and postindex hospitalization and/or ED events was observed. In this managed care population, patients treated with ICSs or LMs had similar measures of treatment effectiveness, as measured by asthma-related health care resource use.

Cysteinyl leukotrienes induce IL-4 release from cord blood-derived human eosinophils.

BACKGROUND: Eosinophils contain preformed stores of IL-4 within their cytoplasmic granules, but physiologic stimuli to release IL-4 from eosinophils are not yet defined. OBJECTIVE: We evaluated whether cysteinyl leukotrienes (CysLTs) could elicit IL-4 release from eosinophils. METHODS: We used a dual-antibody capture and detection assay (EliCell) for IL-4 release and used eosinophils differentiated in vitro from human cord blood-derived progenitors. RESULTS: Leukotriene (LT) C4, LTD4, and LTE4 each elicited the rapid, vesicular transport-mediated, dose- and time-dependent release of IL-4 from eosinophils. Both LTD4 and LTE4 evoked similar and earlier IL-4 release than LTC4. LTC4 did not act directly but only after conversion to LTD4 because an inhibitor of gamma-glutamyl transpeptidase, acivicin, blocked LTC4-induced IL-4 release. MK571 and LY171833, receptor antagonists for CysLT1 and not CysLT2, and pertussis toxin inhibited LTC4-, LTD4-, and LTE4-induced IL-4 release. Cord blood-differentiated eosinophils contained CysLT1 protein detectable by means of immunoblotting. CONCLUSION: CysLTs acting through G(i) protein-coupled and MK571- and LY171833-inhibitable receptors on cord blood-derived human eosinophils can act as autocrine or paracrine mediators to stimulate the rapid, nonexocytotic release of preformed IL-4.

12(S)-Hydroperoxy-eicosatetraenoic acid increases arachidonic acid availability in collagen-primed platelets.

Lipid hydroperoxides have been reported to regulate cell function and eicosanoid formation. The aim of the present study was to determine the effect of 12(S)-hydroperoxy-eicosatetraenoic acid [12(S)-HPETE], the platelet 12-lipoxygenase-derived hydroperoxide of arachidonic acid (AA), on the availability of nonesterified AA, which represents a rate-limiting step in the biosynthesis of eicosanoids. The coincubation of human platelets with concentrations of 12(S)-HPETE below 50 nM and subthreshold concentrations (STC) of collagen (less than 0.24 microg/ml) significantly enhanced platelet aggregation and the formation of thromboxane B(2), the stable catabolite of the potent aggregating agent thromboxane A(2). In addition, the nonesterified endogenous AA concentration increased by 3-fold. Arachidonoyl-containing molecular species concentrations of 1,2-diacyl-glycero-3-phosphocholine, 1-alkyl-2-acyl-glycero-3-phosphocholine, and 1-alkenyl-2-acyl-glycero-3-phosphoethanolamine decreased specifically in response to 12(S)-HPETE, whereas no significant changes were observed within 1,2-diacyl-glycero-3-phosphoethanolamine and 1,2-diacyl-glycero-3-phosphoinositol molecular species. The 12(S)-HPETE-induced increase in nonesterified AA was fully prevented by arachidonoyl trifluoromethyl ketone, an inhibitor of cytosolic phospholipase A(2) (cPLA(2)), and cPLA(2) was translocated to membranes and phosphorylated in platelets incubated with 12(S)-HPETE. In conclusion, these results indicate that nanomolar concentrations of 12(S)-HPETE could play a significant role in controlling the level of endogenous AA and the formation of thromboxane, thereby potentiating platelet function.

Endothelium is required for 12-hydroperoxyeicosatetraenoic acid-induced vasoconstriction.

The pharmacological effects of 12-hydroperoxyeicosatetraenoic acid (12-HPETE) were examined using isolated canine basilar artery segments and isometric tension recording. 12-HPETE produced transient contraction of the artery segment while arachidonic acid or 12-hydroxyeicosatetraenoic acid (12-HETE) had a much lower potency. 12-HPETE-induced contraction which showed a requirement of a functional endothelium and a rapid insensitivity to re-administered 12-HPETE, was completely inhibited by the potassium channel blocker, glibenclamide. Other hydroperoxides did cross-desensitize the 12-HPETE-induced contraction, however, arachidonic acid or 12-HETE did not affect markedly. Here, we present that 12-HPETE is involved in the regulation of vascular tension via its effects on the endothelium.

Studies of in vitro skin permeation and retention of a leukotriene antagonist from topical vehicles with a hairless guinea pig model.

A leukotriene antagonist [Ro 23-3544; 6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid; 1] was studied in vitro for its permeation through and retention in hairless guinea pig skin from various topical vehicles. Both the free acid and the sodium salt forms of the drug were used. The vehicles evaluated were polyethylene glycol 400, propylene glycol, dimethyl sulfoxide (DMSO), C12-C15 alcohol lactates, dimethyl isosorbide, butyrolactone, methylpyrrolidone, hexyl laurate, isopropyl myristate, and caprylic/capric triglyceride (Neobee M5). For the salt form of the drug, the highest permeability coefficient and retention were obtained from DMSO and methylpyrrolidone, respectively. For the acid form, however, the highest permeability coefficient and retention were obtained from hexyl laurate and DMSO, respectively. The highest permeation and retention values were not obtained from the same vehicle for either the salt or the acid form of the drug. This observation questions the validity of using permeation (flux) measurements to screen topical drugs and formulations. Although the precise reasons for this lack of correlation between permeation and retention are not known at this time, this study has shown that the solubility parameters of the drug and the vehicles used may play an important role. It seems logical to conduct skin retention studies rather than flux measurements in evaluating drug delivery from dermatological products.

Peptide leukotriene antagonistic activity of AS-35, a new antiallergic drug.

The effects of 9-[(4-acetyl-3-hydroxy-2-n-propylphenoxy) methyl]-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (AS-35), a newly synthesized compound, on leukotrienes (LTs) antagonistic activities were investigated in vitro and in vivo. In isolated guinea pig preparations, AS-35 antagonized LTC4-, LTD4- and LTE4-induced contractions of the ileum with IC50 values of 8 nM, 4 nM and 3 nM, respectively. In the trachea, the agent also antagonized LTD4- and LTE4-induced contractions with IC50 values of 10 nM and 20 nM, respectively. However, LTC4-induced tracheal contraction in the presence of L-serine borate was not antagonized by AS-35. Histamine-, acetylcholine-, serotonin- and bradykinin-induced contractions of the ileum, carbachol-, prostaglandin D2-, prostaglandin F2 alpha-induced contractions of the trachea and LTB4-induced chemotaxis of rat polymorphonuclear leukocytes were not inhibited by AS-35. As to the in vivo models, AS-35 (i.v.) dose-dependently antagonized bronchoconstriction induced by i.v.-injection of LTC4 and LTD4 in anesthetized guinea pigs, but did not inhibit histamine-induced bronchoconstriction. Oral administration of AS-35 also antagonized LTD4- as well as antigen-induced LT-mediated bronchoconstriction. In addition, LTD4-induced increase in the cutaneous vascular permeability of guinea pig was inhibited by the drug (p.o.). These results indicate that AS-35 is an orally effective, potent and selective peptide LT antagonist.

Leukotriene antagonist S 872419 A for early-phase treatment of chemical burn in the rabbit eye.

S 872419 A, a specific receptor antagonist of peptide leukotrienes, was tested in the early-phase treatment of chemically burned eye (0.25 mol/l sodium hydroxide) of the rabbit. The drug was topically applied 5 times a day in a 1% solution, controls were the untreated opposite eye. Gross and microscopic investigations indicated that S 872419 A inhibits the inflammatory response of the chemically burned anterior eye segment. The parameters of healing considered (epithelial regeneration, corneal clouding and swelling, infiltration with polymorphonuclear leukocytes) suggest inhibition of lipoxygenase-mediated reactions in the tissue. PGF2 alpha levels were the same in aqueous humour of treated and untreated eyes. Further experiments with S 872419 A and other nonsteroidal drugs should improve the anti-inflammatory therapy of the chemically burned eye.

Time-dependent differences in the vasopermeability response to intradermal peptidoleukotrienes.

The time course of extravascular albumin accumulation responses elicited by the leukotrienes LTC4, LTD4, LTE4, and histamine in the skin were compared in the conscious guinea pig. During the initial 15-min period, comparison of the dose-response curves revealed that histamine produced a much larger increase in extravascular albumin content than any of the leukotrienes. One hour after intradermal injection and at subsequent time intervals, the response to LTD4 had increased in magnitude so that it equaled the response produced by histamine. This was apparent from comparison of the time courses of extravascular albumin accumulation for intermediate doses of LTD4 and histamine and also from comparison of dose-response relationships at 4 h post intradermal injection. In contrast to LTD4, the magnitude of the microvascular permeability responses to LTC4 and LTE4 remained relatively small even over an extended time scale. Although histamine produced a large initial response, this also remained essentially unchanged over a 4-h period. It appears that LTD4 may produce a unique, time-dependent cutaneous microvascular permeability response and measurements over 15-30-min periods may underestimate its activity as a vasopermeability factor. The time-dependent effects of LTD4 on albumin extravasation cannot be ascribed to leukocyte infiltration into the skin since LTC4, LTD4, and LTE4 were entirely without effect in this regard.

High yield enzymatic conversion of intravascular leukotriene A4 in blood-free perfused lungs.

Experiments to investigate the fate of intravascularly administered leukotriene (LT) A4, an unstable intermediate of LT generation, were performed in isolated, ventilated, and blood-free perfused rabbit lungs. LT extracted from the lung effluent were separated by different reverse phase and straight phase HPLC procedures as methylated and nonmethylated compounds. Identity of eluting LT was confirmed by UV spectrum analysis and immunoreactivity. Pulmonary artery injection of 75 to 300 nmol of LTA4 resulted in the rapid appearance of cysteinyl-LT as well as LTB4 in the recirculating perfusate. The yield of these enzymatically generated LTA4 metabolites vs non-enzymatic hydrolysis products (6-trans-LTB4, 5-trans-epi-LTB4, 5,6-dihydroxyeicosatetraenoic acids) ranged above 90%. Experiments with application of tritiated LTA4 showed exclusive origin of the detected LT from the exogenously applied precursor. The time course of cysteinyl-LT appearance in the perfusate suggested metabolism of LTC4 via LTD4 to LTE4, whereas there was no evidence for LTB4 omega-oxidation. In the dose range of LTA4 used, the enzymatic conversion of this LT precursor did not approach saturation. Collectively, these data indicate that the intact pulmonary vasculature contains a hitherto not described capacity for enzymatic conversion of intravascularly offered LTA4 to both cysteinyl-LT and LTB4. This may be of biological significance for a putative transcellular biosynthesis of LT in the pulmonary microcirculation upon contact with LTA4 feeder cells, such as activated granulocytes.